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Clinical Approach to Abnormal Liver Enzyme Tests         Liver Cirrhosis Rx 2005                                                

Prevalence of abnormal liver enzyme tests during asymptomatic screening is not uncommon, estimated to be 1-4% by some author (Scand J Gastroenterol 1986;21:106 Hultcrantz R), and is up to one-third of patients screened by others (Mayo Clin Proc 1996; 71:1089 Patrick S. Kamath).

History:

• symptoms of liver disease as anorexia, nausea, vomiting, fatigue, right upper quadrant abdominal pain, jaundice, pruritis, low grade fever, dark-colored urine, clay-colored stools.
• past history of hepatitis, alcohol or drug/medication use, transfusion, travel, unusual diet (raw oyster, mushroom, etc.), sexual history.
• family history of liver disease as Gilbert's syndrome, Wilson's disease, hemochromatosis, or alpha 1-antitrypsin deficiency, viral hepatitis.
• Other medical illnesses like cardiac disease, inflammatory bowel disease, diabetes, arthritis, thyroid diseases, etc.

Physical Examination:

• Signs of liver disease as jaundice, palmar erythema, spider nevi, parotid enlargement, ascites, hepatosplenomegaly, encephalopathy, abdominal tenderness; Kayser-Fleischer rings of Wilson's disease, etc.

Clinical Assessment of the elevated ALT, AST Patients

1. History & Physical Examination, & repeat to confirm elevation of liver enzyme tests
2. If asymptomatic, & no elevated alk.phosphatase or bilirubin, may recheck in 3-6 months.
   If ALT >3-5x or duration > 6months, approach according to the disease suspected (risk factors)
   • Alcohol or drug related: recheck after 6-8 weeks of abstinence.
   • Viral hepatitis: check for hepatitis B or C serology markers.
   • Nonalcoholic steatohepatitis: liver ultrasound or CT scan.
   • Autoimmune: ANA, smooth muscle antibody, antimitochondrial antibody.
   • Wilson's disease: slit lamp eye exam, copper & ceruloplasmin level.
   • Hemochromatosis: ferritins, % iron saturation
   • Alpha 1-antitrypsin deficiency: alpha 1 antitrypsin level
3. Consider liver biopsy if still abnormal.

Interpretation of abnormal aminotransferase/transaminase (ALT, AST) elevation:

• It suggests hepatocellular damage.
• Elevation of AST > ALT, especially if > 2x, suggests alcoholic hepatitis.
• Elevation of AST < ALT is usually seen in viral hepatitis.
• In choledocholithiasis, an AST increase is the earlist abnormality detected, & usually < 5X.  The AST increase is typically transient & returns to normal within 72 hours.
• In cholangitis, the AST increase can be up to 10-fold.
• In viral and drug-induced hepatitis, the AST, ALT levels steadily increase and peak in the low thousands range within 7-14 days.  In uncomplicated viral hepatitis, the transaminases return to normal in about 6 weeks.
• In ischemic hepatitis, the transaminase abruptly increase within 24 hours and may even be higher than 10,000 IU/L.
• In acetaminophen overdose or in herpes simplex hepatitis, the transaminase increases greater than 10,000 IU/L are also noted.
• Many medications can cause increases in AST, such as acetaminophen, NSAID, ACE-inhibitors, nicotinic acid, isoniazid, sulfonamides, erythromycin, anti-fungal agents as griseofulvin & fluconazole.
• Alcoholic or Nonalcoholic Steatohepatitis  (NASH) & hyperthyroidism & hypothyroidism can also cause increased AST< ALT.

Clinical Assessment of the elevated alkaline phosphatase & GGT Patients

1. If alk.phos < 2X, < 6 months, & asymptomatic low risk patients, recheck test in 3-6 months.
   If disease is suspected, check ultrasound or CT scan of liver & biliary tract, then ERCP or liver biopsy as needed.
2. If alk.phos > 2X, > 6 months, or symptomatic, check liver/bilirary tract ultrasound,
   if there is biliary dilatation, consider ERCP.
   if no biliary dilatation, consider antimitochondrial antibody & liver biopsy.
3. If suspect alcohol or drug-related: recheck after 6-8 weeks of abstinence.
   If suspect viral hepatitis: viral serology markers.
   If suspect primary biliary cirrhosis: antimitochondrial antibody.
   If suspect primary sclerosing cholangitis: ERCP.
   Then liver biopsy if indicated.

Interpretation Abnormal Alkaline Phosphatase elevation:

• It suggest  hepatobililary disease, can be divided into four categories:
  1.  biliary obstruction,
  2.  intrahepatic cholestasis (drug or viral hepatitis) or extrahepatic cholestasis (gallstones or tumors),
  3.  infiltrative process: localized lesion within the liver (hepatocellular carcinoma or metastatic liver cancer)
       or patchy involvement within the liver (metastatic cancer or granulomatous disease),
  4.  chronic inflammation involving the bile ducts: primary sclerosing cholangitis, or primary biliary cirrhosis.   
  
  It is also elevated in bone disease, pregnancy, hyperthyroidism, lymphoma, hypernephroma, cardiac failure.  Patients with blood group O and B who are secretors can have increased alkaline phosphatase after eating a fatty meal because of the release of the intestinal enzyme, therefore the test must be performed in fasting patients.
  
• Gamma-glutamyltransferase (GGT) test is recommended to confirm the hepatic origin of the elevated alk.phosphatase.  It is the most sensitive marker of biliary tract disease.

Interpretation Abnormal Biblirubin elevation:

• Normally, the total bilirubin level is less than 1.1 mg/DL, & approximately 70% is indirect (unconjugated) bilirubin.
• Unconjugated hyperbilirubinemia (> 80% of the total bilirubin is indirect) suggests hemolysis or Gilbert's syndrome.  The bilirubin level is usually < 6.0 mg/DL.;
• Conjugated hyperbilirubinemia (> 50% of the total bilirubin is direct) suggests hepatocellular dysfunction or cholestasis.
  When the bilirubin level is > 25-30 mg/dL, extrahepatic cholestasis is an unlikely diagnosis, because the predominantly conjugated bilirubin is water soluble, it is excreted easily by the kidney in extrahepatic cholestasis.

• Common: Chronic viral hepatitis, alcoholic liver disease, nonalcoholic steatohepatitis, medication toxicity, autoimmune hepatitis, genetic hemochromatosis.
• Less Common: Wilson's disease, Alpha 1-antitrypsin deficiency

Cholestatic diseases (elevated alk.phosphatase & GGT)

• Common: Biliary obstruction (gallstones, tumor), drug hepatotoxicity, neoplasms, primary biliary cirrhosis, primary sclerosing cholangitis
• Less Common: autoimmune cholangiopathy, sarcoidosis

Medications with potential for hepatotoxicity

• Hepatocellular abnormalities: allopurinol (granuloma), azathioprine (veno-occlusive disease), NSAID, hydralazine (granuloma), isoniazid, methotrexate (fibrosis), methyldopa, nitrufurantoin (autoimmune-like), quinidine (granuloma).
• Cholestatic abnormalities: Phynytoin (mononucleosis-like synd), sulfa drugs, oral contraceptive, estrogens, erythromycin estolate, captopril, chlorpromazine, anabolic steroids, amoxicillin-clavulanate (Augmentin), & other penicillin derivatives.
• Fatty liver (with or without hepatocellular abnormalities): tetracycline, valproid acid, corticosteroids, amiodarone (phospholipidosis).

Primary Biliary Cirrhosis: antimitochondrial antibody, elevated alk.phosphatase

Autoimmune liver disease: ANA >1:160 especially homogeneous pattern, smooth muscle antibody positivity.

Wilson's disease: low serum copper & cerulopasmin levels, low uric acid, Kayser-Fleischer rings.

Hemochromatosis: transferrin saturation >60% in men, >50% in women, & if the ferritin levels >1,000 ug/L.

Viral hepatitis: positivity of viral serologic markers as Hepatitis A-IgM, Hepatitis BsAg, Hepatitis BcAb (IgM), Hepatitis C Ab.

Extrahepatic cholestasis: diagnosed by liver sonography or CT scan, or ERCP.

Infiltrative liver disease: diagnosed by liver biopsy.

REF:
Cleveland Clin J Med 3/1998; 65:150 - Zobair Younossi
Mayo Clin Proc 11/1996;71:1089 - Patrick S. Kamath         

REF: DynaMed 2009  

Abnormal liver function tests - differential diagnosis

Updated 2009 Mar 20 02:05 PM: elevated serum alanine aminotransferase may be associated with liver disease mortality (Gastroenterology 2009 Feb)

AST and ALT actually reflect hepatocellular injury rather than liver function which is better reflected by albumin and prothrombin time

Elevated AST/ALT (Hepatocellular Injury)

Sources:

• aspartate aminotransaminase (AST) produced by liver, heart, skeletal muscle, kidney, brain, red blood cell
• alanine aminontransaminsase (ALT) produced by liver (more specific for liver injury)

Clinical significance:

• acute injury signified by moderate-to-marked increase (5-10 times upper limit of normal)
• levels > 1,000 units/L correspond to severe liver necrosis or fulminant hepatic failure
• elevated serum alanine aminotransferase may be associated with liver disease mortality  
  

Hepatic causes:

common

Alcohol use disorder (AST/ALT ratio = 2 with AST < 300 units/L and gamma-glutamyl-transpeptidase [GGT] 2 times normal levels)

• Alcoholic hepatitis
• Alcoholic cirrhosis

Cirrhosis

viral hepatitis (aminotransferases peak before jaundice appears)

• Hepatitis A
• Hepatitis B
• Hepatitis C (may have more prominent increase in liver enzymes than other hepatitis viruses)
• Hepatitis D
• Hepatitis E
• Epstein-Barr virus (infectious mononucleosis)
• CMV infection

nonalcoholic fatty liver disease (steatosis/steatohepatitis)

less common

autoimmune hepatitis (liver enzymes mildly elevated)

hemochromatosis (check serum ferritin, iron and transferrin saturation)

alpha-1 antitrypsin (AAT) deficiency

Wilson's disease

hepatic metastatic disease

acute fatty liver of pregnancy

Reye's syndrome

Extrahepatic causes:

obesity - may have mildly elevated ALT and AST

unexplained aminotransferase elevation associated with higher body mass index in study of 15,676 adults in United States 1988-1994 (Am J Gastroenterol 2003 May;98(5):960)

celiac disease

Hemolysis

Muscle injury - AST elevation

Strenuous exercise

Myopathy

idiopathic inflammatory myopathy

hyperthyroidism

diabetes mellitus - 9.5% patients with type 1 diabetes and 12.1% patients with type 2 diabetes had elevated serum alanine aminotransaminase (ALT) levels in study of 1,353 patients with diabetes who did not have excessive alcohol consumption (QJM 2006 Dec;99(12):871)

Macro-AST (complex between normal AST and immunoglobulin)

Medications:

acetaminophen

allopurinol

amiodarone (Cordarone)

amoxicillin/clavulanate

azathioprine

carbamazepine (Tegretol)

cyproheptadine

dantrolene sodium (Dantrium)

fluconazole (Diflucan)

flutamide (Eulexin)

glyburide (Micronase)

heparin

isoniazid (INH)

ketoconazole (Nizoral)

HMG-CoA reductase inhibitors (statins)

labetalol (Normodyne)

methotrexate

methyldopa

nitrofurantoin (Furadantin)

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac, piroxicam

phenytoin (Dilantin)

Propylthiouracil

protease inhibitors

Sulfonamides

tetracycline

trazodone (Desyrel)

valproate/divalproex

Herbs and supplements:

Chaparral leaf (Larrea tridentata)

Ephedra

Gentian

Germander (Teucrium chamaedrys)

Jin bu huan

Kava

Ma huang

Mistletoe (Viscum album)

Scutellaria (skullcap)

Senna (Cassia angustifolia)

Shark cartilage

Vitamin A

Toxins:

industrial solvents

dimetylformamide

2-nitropropane

1,1,1-trichloroethane

trichloroethylene

beryllium - associated with granulomatous hepatitis

copper - associated with granulomatous hepatitis